Among diabetics, peripheral neuropathy is common and ultimately accounts for significant morbidity. The ultimate consequence of such sensory deficits involving the lower extremities may be foot ulceration initiated by trauma that is inapparent to the pt. Such ulcerations often lead to lower extremity amputation, a complication that is 15 times higher in diabetic versus non-diabetic pts. Preliminary clinical studies have demonstrated improvement in signs and symptoms of sensory neuropathy in pts with lower extremity vascular occlusive disease following intramuscular injection of naked DNA encoding vascular endothelial growth factor (VEGF). To determine if such a strategy could be applied to diabetic pts, including those without evidence of large vessel occlusive disease, we investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. In two different animal models of diabetes, nerve blood flow and the number of vasa nervorum were found to be markedly attenuated resulting in severe peripheral neuropathy. In contrast, following VEGF gene transfer, vascular and blood flow in nerves of treated animals were similar to those of non-diabetic controls; constitutive over-expression of VEGF resulted in restoration of large and small fiber peripheral nerve function. These findings implicate microvascular disruption as the basis for diabetic neuropathy and suggest that angiogenic growth factors may constitution a novel treatment strategy for this pernicious disorder. Accordingly, we now seek to address the following two specific aims: 1. Specific Aim #1: To evaluate the safety and impact of VEGF gene transfer on sensory neuropathy in pts with diabetes and associated lower extremity macrovascular disease; and 2. Specific Aim #2: To evaluate the safety and impact of VEGF gene transfer on sensory neuropathy in pts with diabetes without lower extremity macrovascular disease.